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Introduction Despite the implementation of new therapeutic agents, management of relapsed multiple myeloma (MM) remains a challenge. Salvage autologous hematopoietic cell transplant (AHCT) remains a valid therapeutic option for eligible patients who achieve prolonged response after a first AHCT. However, a second graft is not always available, and these patients may need a second mobilization. Patients and Methods This prospective, non-interventional, multicenter study aimed to collect data on the feasibility of salvage AHCT using a plerixafor-based hematopoietic cell mobilization in relapsed MM, according to the plerixafor label in France. Adult patients with relapsed MM eligible for a second AHCT and mobilized using granulocyte- colony stimulating factor (G-CSF) and plerixafor were included. Results Of the 23 patients, 17 achieved a successful hematopoietic cell mobilization and 13 were able to proceed to a second AHCT. Median age was 62.9 years (min–max 51–71). Ten patients (77%) were male. Eleven (85%) received AHCT as a third-line treatment or more. Median time between first and second AHCT was 5.4 years (range, 2.6–16.3). Among 18 evaluable patients, mobilization was successful for 17 (94%) of them [95% CI 84–100], with no reported side effects. Among the 13 patients who underwent salvage AHCT, the median time to engraftment was 14 days (min–max 11–29). One-year progression-free and overall survival were 88.9% [95% CI 43.3–98.4] and 100%, respectively. Conclusion This study demonstrated that plerixafor allows safe and efficient mobilization in relapsed MM patients who are candidates for a salvage AHCT. Trial Registration NCT02439476 Registered 8 May 2015, https://clinicaltrials.gov/ct2/show/NCT02439476.

International audience; Introduction Acute graft-versus-host disease (aGvHD) is a major source of mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Standard 1st line therapy for the treatment of aGvHD involves corticosteroids (CS). However, more than 50% of patients are refractory to CS (SR-aGvHD) and the associated mortality rate is of up to 80%. Recently, Ruxolitinib has been approved as 2nd line treatment for SR-aGvHD. However, patients with severe gastrointestinal (GI) aGvHD seem less likely to respond to Ruxolitinib and have poor outcomes with limited therapeutic options.In this context, fecal microbiotherapy has shown promising results in several pilot studies in patients with refractory GI-aGvHD. Here we report clinical outcomes from 81 patients diagnosed with SR or dependent (SD) GI-aGvHD treated with the pooled allogeneic microbiotherapy MaaT013 as part of the Early Access Program (EAP) in France.Methods 81 patients with SR/SD GI-aGvHD (Classical n=62, late onset n=12, overlap syndrome n=7) were treated with MaaT013 as part of an EAP in France. These patients had failed 1 to 6 prior systemic GvHD treatment lines (median 2; 66/81 received Ruxolitinib). Most patients had grade III-IV aGvHD (11% grade II, 51% grade III, 38% grade IV).For each patient, a total of 3 MaaT013 administrations were planned every 7 +/- 2 days. Each dose comprised 30g of feces in 150 mL of diluent, from 4 to 8 healthy donors, administered by enema (except for 1 patient by nasogastric tube).Treatment response was calculated among all treated patients based on aGvHD staging and grading at day 28 (D28) at the time of the EAP request.Results At D28, the GI-overall response rate (ORR) was 56%: 30 complete response (CR, 37%), 11 very good response rate (VGPR, 14%), 4 partial response (PR, 5%). The GI-ORR was higher in patients with lower grade aGvHD (89% in grade II, 66% in grade III, 32% in grade IV) and higher in SD versus SR patients (92% versus 49%). Including skin and liver symptoms (n=78), response rate was 49%, including 24 CR, 11 VGPR and 3 PR and inversely correlated with aGvHD initial grade (88% in grade II, 55% in grade III, 30% in grade IV).Overall survival (OS) was 51% at 6 months (M6) and 39% at M12. The median follow-up among surviving patients was 355 days (range, 53-731). OS was significantly higher in patients achieving at least GI-PR at D28 (Responder, R; n=45) compared to patients in treatment failure (Non-responder, NR; n=35): 69% versus 28% at M6, 59% versus 14% at M12, respectively. Median survival duration in R was 451 days versus 32 days in NR.Interestingly, aGvHD response was improved in the subgroup of 31 patients previously treated with Ruxolitinib as 2nd line and MaaT013 as 3rd line (65% D28 GI-ORR, OS M6 55% and 49% M12 and 74% versus 15% at M6 and 74% versus 0% at M12 for R and NR respectively).MaaT013 displayed a good overall safety profile in the EAP population: 20 pharmacovigilance cases were reported in 18 patients: sepsis in 11 patients, C. difficile colitis in 2, E. coli osteoarthritis in 1, G. silvicola in stools from 1, P. aeruginosa sinusitis in 1, appearance of air bubbles in the mesorectum in 1, respiratory distress in 1. No pathogen transmission was reported. In 2 patients, non-pathogenic commensal bacteria isolated following infectious events were detected in the administered MaaT013 batch. Causality could not be formally excluded in these cases.The overall incidence of bacteremia (14%) remains low, compared to an incidence of 31% to 74% in bloodstream infections reported in patients with GI-aGvHD. This suggests that fecal microbiotherapy may have a protective effect on bacterial translocation, but this needs to be confirmed in further clinical trials.47 deaths have been reported; the cause of which was GvHD in 21 patients, severe infection in 13, relapse of underlying malignancy in 6, COVID-19 in 3, hemorrhage during surgery in 1, neurological complications post allo-HCT in 1, and cardiac arrest in 2 patients. No causality link with MaaT013 administration has been identified.Conclusion Overall, EAP clinical data showed that MaaT013 was safe and effective for the treatment of SR/SD-GI-aGvHD especially in patients having previously received ruxolitinib. Interestingly, GI-response to aGvHD correlates with increased OS, suggesting a strong favorable benefit-risk profile for MaaT013. A Phase 3 trial is currently ongoing to confirm these results in ruxolitinib-refractory patients (NCT04769895).

International audience; Background: Patients with solid cancers and hematopoietic malignancy can experience systemic symptoms compatible with adult-onset Still’s disease (AOSD). The newly described VEXAS, associated with somatic UBA1 mutations, exhibits an overlap of clinical and/or biological pictures with auto inflammatory signs and myelodysplastic syndrome (MDS). Objectives: To describe a cohort of patients with signs of undifferentiated systemic autoinflammatory disorder (USAID) concordant with AOSD and MDS/chronic myelomonocytic leukemia (CMML) and the prevalence of VEXAS proposed management and outcome. Methods: A French multicenter retrospective study from the MINHEMON study group also used for other published works with the support of multidisciplinary and complementary networks of physicians and a control group of 104 MDS/CMML. Results: Twenty-six patients were included with a median age at first signs of USAID of 70.5 years with male predominance (4:1). Five patients met the criteria for confirmed AOSD. The most frequent subtypes were MDS with a blast excess (31%) and MDS with multilineage dysplasia (18%). Seven patients presented with acute myeloid leukemia and twelve died during a median follow-up of 2.5 years. Six out of 18 tested patients displayed a somatic UBA1 mutation concordant with VEXAS, including one woman. High-dose corticosteroids led to a response in 13/16 cases and targeted biological therapy alone or in association in 10/12 patients (anakinra, tocilizumab, and infliximab). Azacytidine resulted in complete or partial response in systemic symptoms for 10/12 (83%) patients including 3 VEXAS. Conclusions: Systemic form of VEXAS syndrome can mimic AOSD. The suspicion of USAID or AOSD in older males with atypia should prompt an evaluation of underlying MDS and assessment of somatic UBA1 mutation.

Background Post-transplant cyclophosphamide (PT-Cy) has become a standard of care in haploidentical hematopoietic stem cell transplantation (HSCT) to reduce the risk of graft-versus-host disease. However, data on cardiac events associated with PT-Cy are scarce. Objectives This study sought to assess the incidence and clinical features of cardiac events associated with PT-Cy. Methods The study compared clinical outcomes between patients who received PT-Cy (n = 136) and patients who did not (n = 195), with a focus on early cardiac events (ECE) occurring within the first 100 days after HSCT. All patients had the same systematic cardiac monitoring. Results The cumulative incidence of ECE was 19% in the PT-Cy group and 6% in the no–PT-Cy group (p < 0.001). The main ECE occurring after PT-Cy were left ventricular systolic dysfunction (13%), acute pulmonary edema (7%), pericarditis (4%), arrhythmia (3%), and acute coronary syndrome (2%). Cardiovascular risk factors were not associated with ECE. In multivariable analysis, the use of PT-Cy was associated with ECE (hazard ratio: 2.7; 95% confidence interval: 1.4 to 4.9; p = 0.002]. Older age, sequential conditioning regimen, and Cy exposure before HSCT were also associated with a higher incidence of ECE. Finally, a history of cardiac events before HSCT and ECE had a detrimental impact on overall survival. Conclusions PT-Cy is associated with a higher incidence of ECE occurring within the first 100 days after HSCT. Patients who have a cardiac event after HSCT have lower overall survival. These results may help to improve the selection of patients who are eligible to undergo HSCT with PT-Cy, especially older adult patients and patients with previous exposure to Cy., Central Illustration

International audience

Background More than one-third of patients with acute myeloid leukemia (AML) will relapse after allogenic hematopoietic cell transplant (allo-HCT). The main challenge is to overcome disease resistance to achieve a new complete remission while avoiding excessive toxicity. Gemtuzumab ozogamicin (GO), a conjugate of calicheamicin linked to the humanized monoclonal anti-CD33 antibody, has been used for refractory or relapsed AML with promising response rates, but liver toxicity of GO has long been considered a limiting factor. Patients and Methods We included 18 consecutive patients with AML relapsing after a first allo-HCT and treated with fractioned GO (fGO) and intensive chemotherapy. The median age was 40 years (range, 18-65). Results The overall response rate was 72% (13/18), including 7 complete remissions. No death was attributed to treatment toxicity. The main liver toxicity was transient and consisted of transaminase level elevation and hyperbilirubinemia. No cases of veno-occlusive disease were observed after the GO treatment. From the time of salvage treatment initiation, 1- and 2-year OS rates were 54% (95% confidence interval, 28%-74%) and 42% (95% confidence interval, 19%-63%), respectively. Conclusions Our study suggests the feasibility, efficacy, and safety of an fGO-based salvage regimen combined with intensive chemotherapy in patients with CD33+ AML in the case of early relapse after an allo-HCT.

International audience; Background aims: Corticosteroids are the standard first-line treatment for acute graft-versus-host disease (aGVHD), but they are associated with many complications, and less than half of patients have a sustained response.Methods: To improve outcomes, we performed a retrospective study to analyze the efficacy of the addition of extracorporeal photopheresis (ECP) to low-dose corticosteroids in 37 adult patients (median age, 57 years) with skin-predominant aGVHD (grade I, n = 17; grade II, n = 18; and grade III, n = 2). All patients received ECP in combination with 1 mg/kg prednisone (n = 26) or topical steroids (n = 11).Results: Overall response rate was 81% after a median of three ECP procedures (range, 2–8), including 22 complete responses (CR, 59%) and eight very good partial responses (VGPR, 22%). The 11 patients treated with topical corticosteroids achieved CR. Furthermore, 16 (62%) patients reached prednisone withdrawal at a median of 100 days (range, 42–174 days) after its initiation. Eighteen patients developed chronic GVHD (cGVHD); 11 of them (who were in CR of aGVHD) had a new-onset cGVHD, and seven experienced progressive cGVHD (five non-responding and two VGPR patients). A second-line immunosuppressive treatment was initiated in only five (14%) non-responding patients. With a median follow-up of 31 months (range, 6–57 months) 2-year overall survival and non-relapse mortality were 74% and 11%, respectively.Conclusions: Overall, the combination of low-dose corticosteroids and ECP appear to be safe and effective for first-line treatment of skin predominant aGVHD.

In the original publication, the author Mahmoud Aljurf was omitted from the author list. This author’s affiliation is 'Oncology Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia'. This has been corrected in both the PDF and HTML versions of the original article.

Acute graft-versus-host disease (aGVHD) is a common complication of allogeneic hematopoietic stem cell transplantation (alloHCT) and is a major cause of morbidity and mortality. Systemic steroid therapy is the first-line treatment for aGVHD, although about half of patients will become refractory to treatment. As the number of patients undergoing alloHCT increases, developing safe and effective treatments for aGVHD will become increasingly important, especially for those whose disease becomes refractory to systemic steroid therapy. This paper reviews current treatment options for patients with steroid-refractory aGVHD and discusses data from recently published clinical studies to outline emerging therapeutic strategies.

We report results of a thiotepa-based conditioning in haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-CY) and antithymocyte globulin (ATG), for unmanipulated peripheral blood stem cell (PBSC) transplants, in 80 patients with hematological malignancies. Patients in complete remission (CR) received a thiotepa-busulfan-fludarabine (TBF) regimen, while patients with relapsed/refractory (R/R) malignancies received a sequential regimen consisting of thiotepa-etoposide-cyclophosphamide (TEC) and reduced-intensity conditioning (RIC). The median age was 52 (range, 17-72) years, 44% patients had R/R disease at transplant, and the median follow-up was 417 (range, 180-1595) days. The median days to neutrophil engraftment was 17 (range, 12-34). The cumulative incidences (CI) of acute graft-versus-host disease (GVHD) grade III to IV, severe chronic GVHD, nonrelapse mortality (NRM), and relapse were 16%, 16%, 26, and 26%, respectively. The 2-year overall survival (OS) and disease-free survival (DFS) were 53% and 47%, respectively. There were no significant differences between the patients in CR and R/R patients in terms of engraftment, GVHD, NRM, relapse, OS, or DFS. We conclude that thiotepa-based regimen with PT-CY can be modified with PBSC and ATG, still providing low toxicity, protection against GVHD, and low relapse incidence. Particularly encouraging are the results with the modification to sequential regimen in R/R patients.

Plasmacytoid dendritic cells (pDCs) are a unique subset of dendritic cells specialised in secreting high levels of type I interferons. pDCs play a crucial role in antiviral immunity and have been implicated in the initiation and development of many autoimmune and inflammatory diseases. This review summarises the latest advances in recent years in several aspects of pDC biology, with special focus on pDC heterogeneity, pDC development via the lymphoid pathway, and newly identified proteins/pathways involved in pDC trafficking, nucleic acid sensing and interferon production. Finally, we also highlight the current understanding of pDC involvement in autoimmunity and alloreactivity, and opportunities for pDC‐targeting therapies in these diseases. These new insights have contributed to answers to several fundamental questions remaining in pDC biology and may pave the way to successful pDC‐targeting therapy in the future., This review summarises the latest advances in several aspects of plasmacytoid dendritic cell (pDC) biology, with a special focus on pDC heterogeneity, pDC development via the lymphoid pathway, and newly identified proteins/pathways involved in pDC trafficking, nucleic acid sensing and interferon production. We also highlight the current understanding of pDC involvement in autoimmunity and alloreactivity, and opportunities for pDC‐targeting therapies in these diseases.

International audience; Humans share a core intestinal microbiome and yet human microbiome differs by genes, species, enterotypes (ecology), and gene count (microbial diversity). Achievement of microbiota metagenomic analysis has revealed that the microbiome gene count is a key stratifier of health in several immune disorders and clinical conditions. We review here the progress of the metagenomic pipeline analysis, and how this has allowed us to define the host–microbe symbiosis associated with a healthy status. The link between host–microbe symbiosis disruption, the so-called dysbiosis and chronic diseases or iatrogenic conditions is highlighted. Finally, opportunities to use microbiota modulation, with specific nutrients and/or live microbes, as a target for personalized nutrition and therapy for the maintenance, preservation, or restoration of host–microbe symbiosis are discussed.

Arsenic trioxide (As2O3) is recently found to have therapeutic potential in systemic sclerosis (SSc), a life-threatening multi-system fibrosing autoimmune disease with type I interferon (IFN-I) signature. Chronically activated plasmacytoid dendritic cells (pDCs) are responsible for IFN-I secretion and are closely related with fibrosis establishment in SSc. In this study, we showed that high concentrations of As2O3 induced apoptosis of pDCs via mitochondrial pathway with increased BAX/BCL-2 ratio, while independent of reactive oxygen species generation. Notably, at clinical relevant concentrations, As2O3 preferentially inhibited IFN-α secretion as compared to other cytokines such as TNF-α, probably due to potent down-regulation of the total protein and mRNA expression, as well as phosphorylation of the interferon regulatory factor 7 (IRF7). In addition, As2O3 induced a suppressive phenotype, and in combination with cytokine inhibition, it down-regulated pDCs’ capacity to induce CD4+ T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. Moreover, chronically activated pDCs from SSc patients were not resistant to the selective IFN-α inhibition, and regulatory phenotype induced by As2O3. Collectively, our data suggest that As2O3 could target pDCs and exert its treatment efficacy in SSc, and more autoimmune disorders with IFN-I signature., Graphical abstract High concentrations of As2O3 induce apoptosis of plasmacytoid dendritic cells (pDCs) with increased BAX/BCL-2 ratio. At clinical relevant concentrations, As2O3 preferentially inhibits IFN-α secretion via down-regulation of interferon regulatory factor 7 expression, and down-regulates pDCs’ capacity to induce T and B cell responses. Moreover, the As2O3 effects on pDCs were uncompromised in systemic sclerosis patients.Image 1

Thirty patients, with high-risk acute myeloid leukemia (AML, n = 20) or myelodysplastic syndrome (MDS, n = 10), were enrolled in a phase II trial entailing prophylactic post-transplant azacitidine (AZA) plus escalated doses of donor lymphocyte infusion (DLI). The median number of AZA cycles was 5 (1-12) with 10 patients (33%) completing the 12 projected cycles. DLI were performed in 17 patients: 5 received one DLI, 2 received 2 DLI and 8 received 3 infusions. AZA was well tolerated, but discontinued in 20 patients primarily due to graft-versus-host disease (GvHD) and relapse. The cumulative incidence (CI) of grade 1-3 acute GvHD was 31.5% and the chronic GvHD CI was 53% at 2 years. At a median follow-up of 49 months (27-63), 18 patients are alive. The overall and disease-free survivals are 65.5% (CI 95% = 48.2-82.8) at 2 years. Cause of death was mainly relapse for 9 patients. The median time to relapse was 7 months (2.5-58) and the cumulative incidence of relapse at 2 years was 27.6% (CI 95% = 12.8-44.6). These results confirm that AZA is well tolerated as a prophylactic treatment to reduce the risk of post-transplantation relapse and compared favorably to those of patients who receive no post-transplant maintenance.

International audience; Acute graft-versus-host disease (aGVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT). The majority of aGVHD mouse models are based on radiation conditioning and bone marrow as graft, despite that most allo-HCTs performed now in clinic are based on chemotherapy conditioning and G-CSF mobilized graft. Aiming for a higher translational value, we constructed an MHC major mismatched [C57BL/6 (H-2 Kb) to BALB/c (H-2Kd)] aGVHD mouse model based on busulfan/cyclophosphomide (BU–CY) conditioning and human G-CSF mobilized splenocytes as graft. Allogeneic transplanted mice showed quick and profound donor engraftment. Moreover, there were quick onset (day +7) of typical clinical and histopathological signs of aGVHD, which gradually developed to extensive aGVHD. In addition, CD8+ T cells were the main aGVHD contributing T-cell subtype. No toxicity or GVHD signs were observed in the syngeneic setting. This clinical-relevant model offers a promising platform for future studies on aGVHD.

Introduction. AML standard intensive induction chemotherapy ("3+7" or equivalent) combined with wide spectrum antibiotics can dramatically alter the composition of the gut microbiota, leading to dysbiosis which is characterized by loss of microbial diversity. Such dysbiosis status can promote a pathological condition involving uncontrolled local immune responses, systemic inflammation and increased incidence of adverse events. The development of FMT-based drugs to restore microbial communities could offer novel therapeutic possibilities to reduce such adverse events and potentially improve outcomes in AML. We therefore conducted this single arm prospective phase I/II multicenter trial (NCT02928523) to evaluate the use of a FMT-based drug in association with AML induction treatment to restore the gut microbiota diversity. Patients and methods. A total of 62 consecutive patients aged between 24 and 69 years old with a diagnosis of de novo AML were screened in 7 French sites. At time of admission and AML diagnosis (Step 1=S1), patients' faeces were collected, rigorously screened, prepared following a standardized process, and stored at -80°C until later administration. The drug was administered as an enema after hematopoietic recovery (S2) and before consolidation chemotherapy (Conso). The primary endpoint was the recovery of at least 70% of microbiota diversity (based on the Simpson index) after drug administration and the reduction of multidrug resistant bacteria carriage. Blood and feces samples were collected at S1, S2, and around 10 days post-FMT before Conso (S3). Microbiome diversity restoration was assessed by metagenomics analysis through Illumina HiSeq shotgun sequencing. Antibiotic resistance gene carriage (ARGC, also known as resistome) was evaluated through mapping of readouts on the MEGARES database. Secondary objectives included safety and analysis of host response with assessment of blood and fecal markers by ELISA and Luminex. Results. Overall, 25 patients were actually treated with FMT, and 20 were included in the per-protocol population. Induction Chemotherapy (IC) induced a dramatic shift in microbial communities, with a significant 42.3% decrease of mean α-diversity Simpson index between S1 and S2 at species level (0.85 to 0.50; p No serious adverse events (SAE) were observed within 30 days after FMT and all post FMT SAEs were not related to the FMT procedure. Moreover, FMT did not induce any local or systemic inflammatory reaction as measured by fecal and blood markers (fecal neopterin and IgA; plasmatic CRP, IL-6 and sCD14). Interestingly, restoration of the microbiome diversity was associated with a significant reduction of CRP and fecal neopterin levels, suggesting a potential anti-inflammatory impact of FMT. Overall, FMT was well tolerated and had an excellent safety profile. The one-year overall survival estimate in the whole cohort was 84% (4 deaths among 25, none of which were related to FMT: 2 multiple organ failures, 1 heart attack and 1 grade IV resistant GVHD). The median time to death from the second FMT was 182.5 days (113-225 days). Conclusions. This is the first prospective trial testing the safety and efficacy of FMT in AML patients receiving intensive induction chemotherapy. The trial achieved its primary endpoint and established the capacity of FMT to restore a diverse microbiome with high levels of similarity to baseline, as well as reducing ARGC and intestinal inflammation. A controlled randomized trial with repeated FMT administrations is currently planned to further evaluate the impact of FMT on clinical outcomes and long-term survival. (This trial was funded by MaaT Pharma whose product was tested in this protocol). Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria. Doré:MaaT Pharma: Consultancy, Honoraria.

Background Graft-versus-host disease (GVHD) is one of the leading causes of non-relapse mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HCT). Methods We evaluated the outcomes of two well-established strategies used for GVHD prevention: in vivo T cell depletion using antithymocyte globulin (ATG) and ex vivo T cell depletion using a CD34-selected (CD34+) graft. A total of 525 adult patients (363 ATG, 162 CD34+) with intermediate or high-risk cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1) were included. Patients underwent myeloablative allo-HCT using matched related or unrelated donors. Results Two-year overall survival estimate was 69.9% (95% CI, 58.5–69.4) in the ATG group and 67.6% (95% CI, 60.3–74.9) in the CD34+ group (p = 0.31). The cumulative incidence of grade II–IV acute GVHD and chronic GVHD was higher in the ATG cohort [HR 2.0 (95% CI 1.1–3.7), p = 0.02; HR 15.1 (95% CI 5.3–42.2), p

Impact of KIR/HLA genetic combinations on double umbilical cord blood transplantation outcomes. Results of a French multicentric retrospective study on behalf of the Societe Francophone de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) and the Societe Francophone d’Histocompatibilite et d’Immunogenetique (SFHI)

International audience; Late complications (LC) and quality of life (QOL) were analyzed in 110 adult patients who underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) and were alive for more than 2 years after allo-SCT. Overall survival of these patients was 93% (95% confidence interval [CI], 88% to 99%) and 81% (95% CI, 71% to 94%) at 5 and 10 years, respectively. The primary cause of death was a recurrence of primary malignancy. With a median follow-up of 4.6 years (range, 2 to 12.1), chronic graft-versus-host disease (cGVHD) was the most prevalent late effect, with a cumulative incidence of 66% (95% CI, 57% to 74%) at 10 years. Car-diovascular complications were the most prevalent LC with a cumulative incidence of 47% (95% CI, 35% to 59%), followed by pulmonary complications with a cumulative incidence of 33% (95% CI, 21% to 46%) and renal impairment with a cumulative incidence of 34% (95% CI, 25% to 43%) at 10 years. Secondary malignancies occurred with a cumulative incidence of 11% (95% CI, 5% to 20%) at 10 years. In this series, 61 patients (55%) responded to QOL survey. With the use of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 and Functional Assessment of Cancer Therapy–Bone Marrow Transplant questionnaires , most of the patients reported good to excellent QOL and patients with cGVHD had significantly lower QOL than patients without cGVHD. In conclusion, QOL after RIC is comparable to that seen after myeloablative conditioning, while the natural history of LC after RIC appears to be different from that described in the standard myeloablative setting, warranting further research in this field.

International audience; Over the past decade, significant advances have been made in the field of multiple myeloma. Introduction of the so-called novel agents, proteasome inhibitors (PI) and immunomodulatory drugs (IMiD), and improved supportive care have resulted in significantly better outcome. Standard first line treatment in fit patients include PI and IMiD based induction, high dose melphalan with autologous hematopoietic stem cell transplantation (ASCT) and consolidation/maintenance. However, despite these progresses MM remains incurable for the majority of patients and most patients will relapse. Next generation PI (carfilzomib, ixazomib) and IMiD (pomalidomide) and new therapeutic classes: monoclonal antibody (elotuzumab, daratumumab) and pan-deacetylase inhibitors (panobinostat) have been successfully evaluated in relapse multiple myeloma. Some of these new agents are now approved for multiple myeloma treatment at relapse. However choosing the most appropriate treatment at relapse may be difficult. This review sum up the most important studies and provide evidence to choose the most relevant therapeutic strategy for relapse after ASCT, based on disease, patient and previous treatment related parameters.

International audience; Allogeneic stem cell transplantation (allo-SCT) is a curative therapy for different life-threatening malignant and non-malignant hematologic disorders. Acute graft-vs.-host disease (aGVHD) and particularly gastrointestinal aGVHD remains a major source of morbidity and mortality following allo-SCT, which limits the use of this treatment in a broader spectrum of patients. Better understanding of aGVHD pathophysiology is indispensable to identify new therapeutic targets for aGVHD prevention and therapy. Growing amount of data suggest a role for T helper (Th)17 cells in aGVHD pathophysiology. In this review, we will discuss the current knowledge in this area in animal models and in humans. We will then describe new potential treatments for aGVHD along the Th17 axis.

Background: Pre-transplant pulmonary function testing (PFT) is required in all patients eligible for allogeneic stem cell transplantation (allo-SCT). Diffusion lung capacity for carbon monoxide (DLCO) is the main parameter taken into account but the overall impact of this factor is debated. Diffusion lung capacity for nitric oxide (DLNO) may be of higher interest to predict pulmonary complications, because radiotherapy and chemotherapy used to treat patients with haematological diseases affect mostly the alveolar-capillary membrane, which destruction is more appreciate by DLNO than DLCO measure. Also, DLNO/DLCO ratio represents a new index of gas exchange and an alternative way of investigating the alveolar membrane and the blood reacting with the gas. Methods: We considered all patients who received an allo-SCT for hematological malignancies between March 2012 and January 2014 in our department and for whom a pre-transplant PFT, including DLCO and DLNO measures, was validated. Factors influencing pre-transplant DLCO, DLNO and DLNO/DLCO ratio were analyzed as well as impact of those 3 diffusion lung parameters on general outcomes and pulmonary complications (severe pulmonary complications (SPC) defined as any pulmonary complication responsible for hospitalization, pulmonary related mortality (PRM), acute respiratory distress syndrome (ARDS). Results: We included 103 patients (male: n=68, median age at transplant: 58 years) in this study. Majority of them had a myeloid disease (n=67), and were in complete (n=56) or partial (n=23) remission at transplant. Type of donor was: matched related donor (N=35), haploidentical related donor (n=5), matched unrelated donor (n=43), mismatched unrelated donor (n=9) and umbilical cord blood (n=10). First stem cell source used was peripheral blood stem cell (n=83). Eight five percent of patient received a reduced intensity regimen. With a median follow up of 21.5 months (range: 3.8-34.7), 2 year cumulative incidence of overall survival, Disease free survival, relapse incidence, non-relapse mortality, SPC, ARDS and PRM were respectively 65.4% ( 55.2-73.6), 52.5% (42.7-62.2), 31.8% (22.3-41.7), 15.8% (9.4-23.5), 25.4% (17-34), 7.8% (4-14), and 4.9% (1.8-10.4). Normal DLCO and DLNO percentages of predicted normal value (>80%) were documented in 48 and 44 patients, respectively but median percentages for the all cohort were under the normal at transplant: DLCO: 78.9%, DLNO: 78.1%. Median DLNO/DLCO ratio was 5.3 (range: 2.7-8.6). Regarding factors influencing pre-transplant PFT results, DLCO was significantly decreased in patients with respiratory history (72.3% versus 81.5%, p=0.001), in patients having received therapeutic with cardiac or pulmonary toxicities (74.2% versus 80.6%, p=0.02) and in patients over 58 years (81.0% versus 75.4%, p=0.05). Similarly, DLNO was significantly decreased in patients with respiratory history (74.3% versus 80.9%, p=0.03) and in patients' smokers or with history of smoking (75.3% versus 81.8%, p=0.03). Finally, patients' age was the only parameter with a significant impact on DLNO/DLCO (5.5 in patients >58 years versus 5.2 in patients ≤58years, p=0.04). In univariate analysis, a DLNO value Conclusion: DLNO and DLNO/DLCO ratio may be more appropriate to predict pulmonary complications than DLCO alone after allo-SCT. These results have to be confirmed prospectively. Disclosures Mohty: Janssen: Honoraria; Celgene: Honoraria. Moreau:Takeda: Other: Adboard; Amgen: Other: Adboard; Novartis: Other: Adboard; Celgene: Honoraria, Other: Adboard; Janssen: Other: Adboard.

International audience; Our main objective was to determine new factors associated with engraftment and single-unit predominance after double umbilical cord blood (UCB) allogeneic stem-cell transplantation. Engraftment occurred in 78% of cases in this retrospective study including 77 adult patients. Three-year overall survival, disease-free survival, relapse incidence, and nonrelapse mortality were 55 ± 6%, 44 ± 6%, 33 ± 5%, and 23 ± 4%, respectively. In multivariate analysis, Human herpesvirus 6 reactivation during aplasia (hazard ratio [HR] = 2.63; 95% confidence interval [CI]: 1.64-4.17; p < 0.001), younger recipient age (

International audience; Lung function decline is a well-recognized complication following allogeneic SCT (allo-SCT). Reduced-intensity conditioning (RIC) and in vivo T-cell depletion by administration of antithymocyte globulin (ATG) may have a protective role in the occurrence of late pulmonary complications. This retrospective study reported the evolution of lung function parameters within the first 2 years after allo-SCT in a population receiving the same RIC regimen that included fludarabine and i.v. BU in combination with low-dose ATG. The median follow-up was 35.2 months. With a median age of 59 years at the time of transplant, at 2 years, the cumulative incidences of non-relapse mortality was as low as 9.7%. The cumulative incidence of relapse was 33%. At 2 years, the cumulative incidences of extensive chronic GVHD (cGVHD) and of pulmonary cGVHD were 23.1% and 1.9%, respectively. The cumulative incidences of airflow obstruction and restrictive pattern were 3.8% and 9.6%, respectively. Moreover, forced expiratory volume (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio remained stable from baseline up to 2 years post transplantation (P=0.26, P=0.27 and P=0.07, respectively). These results correspond favorably with the results obtained with other RIC regimens not incorporating ATG, and suggest that ATG may have a protective pulmonary role after allo-SCT.

International audience; Allogeneic stem cell transplantation (allo-SCT) is a curative therapy for different life-threatening malignant and nonmalignant hematologic disorders. Graft-versus-host disease (GVHD) remains a major source of morbidity and mortality following allo-SCT, which limits the use of this treatment in a broader spectrum of patients. Early diagnostic of GVHD is essential to initiate treatment as soon as possible. Unfortunately, the diagnosis of GVHD may be difficult to establish, because of the nonspecific nature of the associated symptoms and of the numerous differential diagnosis. This is particularly true regarding gastrointestinal (GI) acute GVHD. In the recent years many progress has been made in medical imaging test and endoscopic techniques. The interest of these different techniques in the diagnosis of GI acute GVHD has been evaluated in several studies. With this background we review the contributions, limitations, and future prospect of these techniques in the diagnosis of GI acute GVHD.

Allogeneic hematopoietic cell transplantation (Allo-HCT) is to date the only curative cell therapy for many patients with hematologic malignancies. The development of acute graft-versus-host disease (GvHD) prophylaxis by intravenous administration of post-transplant cyclophosphamide (PTCy) has enabled the increasing use of haploidentical donor grafts (Haplo-HCT). PTCy, induces a functional impairment of alloreactive T cells, without toxic effects on hematopoietic stem cells. We show that PTCy has a significant and lasting impact on γ/δ T cell reconstitution, up to 1 year after Haplo-HCT. Furthermore, this delay in γ/δ T cell reconstitution directly correlates with an increased risk of developing an increase in EBV viral load after Haplo-HCT. Nevertheless, we find preemptive treatment of increase in EBV viral load with rituximab, induces a delay in the reconstitution of B cells, deep hypogammaglobulinemia and a high risk of rituximab-related neutropenia. This research work on immune reconstitution reveals unrecognized immunomodulatory effects of different therapeutic strategies after Allo-HCT. Indeed, if the results of PTCy in prophylaxis of acute GvHD after Haplo-HCT and of the preemptive administration of rituximab after EBV infection on the other hand are indisputable; better knowledge of the direct effects on immune effectors remains necessary to limit toxicity and optimize uses.; La greffe allogénique de cellules souches hématopoïétiques (Allo-CSH) est à ce jour l’unique thérapie cellulaire curative pour de nombreux patients atteints d’hémopathies malignes. Le développement d’une prophylaxie de la maladie aiguë du greffon contre l’hôte (GvHD) par administration intraveineuse de cyclophosphamide après la greffe (PTCy) a permis le développement de l’utilisation des donneurs haploidentiques (Haplo-CSH). Le PTCy, induit une altération fonctionnelle des lymphocytes T alloréactifs, sans effet toxique sur les cellules souches hématopoïétiques. Nous avons mis en évidence que le PTCy était associé à un retard durable de la reconstitution lymphocytaire T γ/δ, jusqu’à 1 an après Haplo-CSH. Ce délai à la reconstitution lymphocytaire T γ/δ étant associé à un risque accru de présenter une augmentation de la charge virale EBV au décours de l’Haplo-CSH. De plus, nous avons mis en évidence que le traitement préemptif par rituximab dès l’augmentation de la charge virale EBV, induisait un retard à la reconstitution des lymphocytes B, des hypogammaglobulinémies profondes et un risque élevé de neutropénies liées au rituximab. Ces travaux de recherche sur la reconstitution immunitaire révèlent des effets immunomodulateurs méconnus de différentes stratégies thérapeutiques après Allo-CSH. En effet, si les résultats du PTCy en prophylaxie de la GvHD aiguë après Haplo-CSH et de l’administration préemptive de rituximab après infection EBV d’autre part sont indiscutables ; une meilleure connaissance des effets directs sur les effecteurs immunitaires reste nécessaire pour en limiter la toxicité et en optimiser les usages.

Allogeneic hematopoietic cell transplantation (Allo-HCT) is to date the only curative cell therapy for many patients with hematologic malignancies. The development of acute graft-versus-host disease (GvHD) prophylaxis by intravenous administration of post-transplant cyclophosphamide (PTCy) has enabled the increasing use of haploidentical donor grafts (Haplo-HCT). PTCy, induces a functional impairment of alloreactive T cells, without toxic effects on hematopoietic stem cells. We show that PTCy has a significant and lasting impact on γ/δ T cell reconstitution, up to 1 year after Haplo-HCT. Furthermore, this delay in γ/δ T cell reconstitution directly correlates with an increased risk of developing an increase in EBV viral load after Haplo-HCT. Nevertheless, we find preemptive treatment of increase in EBV viral load with rituximab, induces a delay in the reconstitution of B cells, deep hypogammaglobulinemia and a high risk of rituximab-related neutropenia. This research work on immune reconstitution reveals unrecognized immunomodulatory effects of different therapeutic strategies after Allo-HCT. Indeed, if the results of PTCy in prophylaxis of acute GvHD after Haplo-HCT and of the preemptive administration of rituximab after EBV infection on the other hand are indisputable; better knowledge of the direct effects on immune effectors remains necessary to limit toxicity and optimize uses., La greffe allogénique de cellules souches hématopoïétiques (Allo-CSH) est à ce jour l’unique thérapie cellulaire curative pour de nombreux patients atteints d’hémopathies malignes. Le développement d’une prophylaxie de la maladie aiguë du greffon contre l’hôte (GvHD) par administration intraveineuse de cyclophosphamide après la greffe (PTCy) a permis le développement de l’utilisation des donneurs haploidentiques (Haplo-CSH). Le PTCy, induit une altération fonctionnelle des lymphocytes T alloréactifs, sans effet toxique sur les cellules souches hématopoïétiques. Nous avons mis en évidence que le PTCy était associé à un retard durable de la reconstitution lymphocytaire T γ/δ, jusqu’à 1 an après Haplo-CSH. Ce délai à la reconstitution lymphocytaire T γ/δ étant associé à un risque accru de présenter une augmentation de la charge virale EBV au décours de l’Haplo-CSH. De plus, nous avons mis en évidence que le traitement préemptif par rituximab dès l’augmentation de la charge virale EBV, induisait un retard à la reconstitution des lymphocytes B, des hypogammaglobulinémies profondes et un risque élevé de neutropénies liées au rituximab. Ces travaux de recherche sur la reconstitution immunitaire révèlent des effets immunomodulateurs méconnus de différentes stratégies thérapeutiques après Allo-CSH. En effet, si les résultats du PTCy en prophylaxie de la GvHD aiguë après Haplo-CSH et de l’administration préemptive de rituximab après infection EBV d’autre part sont indiscutables ; une meilleure connaissance des effets directs sur les effecteurs immunitaires reste nécessaire pour en limiter la toxicité et en optimiser les usages.

In the recent decades, the successful treatment of arsenic trioxide (As2O3) in mouse models of several autoimmune and inflammatory diseases such as systemic sclerosis (SSc) and chronic graft-versus-host disease (GVHD) has shed light on this old drug as a ‘novel’ immunomodulator. Notably, plasmacytoid dendritic cells (pDCs) play important role in both autoimmunity and alloreactivity. In a first study, we found that high doses of As2O3 induced pDC apoptosis induction through mitochondrial pathway. Clinically relevant doses of As2O3 preferentially inhibited IFN-α secretion and induced regulatory phenotype of both healthy and SSc pDCs. The selective IFN-α inhibition was probably due to potent down-regulation of the transcription factor IRF-7. Moreover, As2O3 impaired the capacity of pDCs to induce CD4+ T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. In a second study, we successfully constructed a new acute GVHD mouse model based on both chemotherapy conditioning and G-CSF mobilized graft, which showed good donor engraftment and typical clinical signs of aGVHD. Furthermore, we showed that gut decontamination delayed the onset of aGVHD in this model.; Lors des dernières décennies, les résultats obtenus par le traitement au trioxyde de diarsenic (As2O3) de divers modèles murins de maladies auto-immunes et inflammatoires, telles que la sclérodermie systémique (SSc), ou de maladie du greffon contre l'hôte (GVHD) ont permis de considérer ce vieux médicament comme un "nouvel" immunomodulateur. Les cellules dendritiques plasmocytoïdes (pDC) jouant un rôle majeur dans l’auto-immunité et l’alloréactivité, nous avons observé dans une première étude que des doses élevées d'As2O3 induisaient l'apoptose des pDC par voie mitochondriale. Les doses, cliniquement pertinentes, d'As2O3 inhibaient préférentiellement la sécrétion d'IFN-α et induisaient un phénotype régulateur des pDC de témoins et de patients atteints de SSc. Cette inhibition sélective de l'IFN-α était probablement liée à une puissante inhibition du facteur de transcription IRF-7. De plus, l’As2O3 altérait leur capacité à induire une prolifération lymphocytaire T CD4+, la polarisation Th1/Th22 et la différenciation des lymphocytes B en plasmablastes. Dans une seconde étude, nous avons développé un nouveau modèle murin de GVHD aigue, basé à la fois sur un conditionnement par chimiothérapie et sur un greffon mobilisé par G-CSF. Ce modèle a montré une bonne prise de greffe des cellules du donneur et des signes cliniques typiques de GVHD aigue. De plus nous avons montré qu’une décontamination bactérienne du tube digestif retardait l’apparition d’une GVHD aigue.

In the recent decades, the successful treatment of arsenic trioxide (As2O3) in mouse models of several autoimmune and inflammatory diseases such as systemic sclerosis (SSc) and chronic graft-versus-host disease (GVHD) has shed light on this old drug as a ‘novel’ immunomodulator. Notably, plasmacytoid dendritic cells (pDCs) play important role in both autoimmunity and alloreactivity. In a first study, we found that high doses of As2O3 induced pDC apoptosis induction through mitochondrial pathway. Clinically relevant doses of As2O3 preferentially inhibited IFN-α secretion and induced regulatory phenotype of both healthy and SSc pDCs. The selective IFN-α inhibition was probably due to potent down-regulation of the transcription factor IRF-7. Moreover, As2O3 impaired the capacity of pDCs to induce CD4+ T cell proliferation, Th1/Th22 polarization, and B cell differentiation towards plasmablasts. In a second study, we successfully constructed a new acute GVHD mouse model based on both chemotherapy conditioning and G-CSF mobilized graft, which showed good donor engraftment and typical clinical signs of aGVHD. Furthermore, we showed that gut decontamination delayed the onset of aGVHD in this model., Lors des dernières décennies, les résultats obtenus par le traitement au trioxyde de diarsenic (As2O3) de divers modèles murins de maladies auto-immunes et inflammatoires, telles que la sclérodermie systémique (SSc), ou de maladie du greffon contre l'hôte (GVHD) ont permis de considérer ce vieux médicament comme un "nouvel" immunomodulateur. Les cellules dendritiques plasmocytoïdes (pDC) jouant un rôle majeur dans l’auto-immunité et l’alloréactivité, nous avons observé dans une première étude que des doses élevées d'As2O3 induisaient l'apoptose des pDC par voie mitochondriale. Les doses, cliniquement pertinentes, d'As2O3 inhibaient préférentiellement la sécrétion d'IFN-α et induisaient un phénotype régulateur des pDC de témoins et de patients atteints de SSc. Cette inhibition sélective de l'IFN-α était probablement liée à une puissante inhibition du facteur de transcription IRF-7. De plus, l’As2O3 altérait leur capacité à induire une prolifération lymphocytaire T CD4+, la polarisation Th1/Th22 et la différenciation des lymphocytes B en plasmablastes. Dans une seconde étude, nous avons développé un nouveau modèle murin de GVHD aigue, basé à la fois sur un conditionnement par chimiothérapie et sur un greffon mobilisé par G-CSF. Ce modèle a montré une bonne prise de greffe des cellules du donneur et des signes cliniques typiques de GVHD aigue. De plus nous avons montré qu’une décontamination bactérienne du tube digestif retardait l’apparition d’une GVHD aigue.